(a) Field of the Invention
This invention relates to a method for alleviating diseases in animals which are susceptible to treatment by stimulation of the cell-mediated immune response system comprising administering to a diseased animal a 1-substituted-pyrrole derivative and to compositions useful therefor.
(b) Description of the Prior Art
The use of immuno modulators which affect the immune response system in such a way as to combat diseases in animals which are susceptible to treatment by immuno modulators is well known. For example, bacterial or viral infections, such as Staphylococcus aureus and Herpes simplex virus, Type 2, (HSV2), have been successfully treated with levamisole [(1)-2,3,5,6-tetrahydro-6-phenylimidazo[2,1-b]thiazole; Fischer et al., J. Infect. Diseases, 132, 578-581 (1975)]. The remission or control of certain forms of cancer has been achieved with BCG vaccine (Bacillus of Calmette and Guerin, a strain of Mycobacterium bovis) [Holmes et al., J.A.M.A., 232, 1052-1055 (1975)], an immunologic adjuvant, or with levamisole [Brit. Med. Jour., 3, 461-464 (1975)], whose immuno stimulant properties in other areas is well known as indicated above. Levamisole has also been shown to have some effect in the treatment of rheumatoid arthritis by stimulation of cell-mediated immunity [Huskisson et al., The Lancet, I, 393-395 (1976)].
Other immuno stimulants disclosed by the art are: "a . . . water-soluble substantially neutral polymer of acrylic acid cross-linked with . . . polyalkyl-sucrose or polyalkylpentaerythritol . . . " PA1 "a macromolecular synthetic resin complexing material such as an acrylic acid polymer cross-linked with a polyalkyl saccharide . . . "
[Lund, U.S. Pat. No. 3,920,811, patented Nov. 18, 1975]; a nucleotide or complex of polynucleotides [Hilleman et al., U.S. Pat. No. 3,906,092, patented Sept. 16, 1975]; and
[Glass et al., U.S. Pat. No. 3,919,411, patented Nov. 11, 1975].
The 1-substituted-pyrrole derivatives used in the practice of this invention having the formulas I, II, III and IV below have been disclosed, together with their in vitro antibacterial activity in Belgian Pat. No. 816,542, and each of the compounds of Formulas I, II, III, IV and V, and the anti-tubercular activity of two of them, i.e. Compounds I and III, have been disclosed in Johnson U.S. Pat. No. 4,051,147, as well as in divisional application thereof, Ser. No. 730,162, filed Oct. 7, 1976, and now U.S. Pat. No. 4,138,405. Compounds I, II, III and V are claimed in U.S. Pat. No. 4,138,405, and Compound IV is claimed in U.S. Pat. No. 4,051,147. The compounds are disclosed in both U.S. Pat. No. 4,051,147 and U.S. Pat. No. 4,138,405 to be useful as in vitro antibacterial agents against a variety of microorganisms. Two of the species (Compounds I and III) are also there disclosed to be effective against systemic Mycobacterium tuberculosis infections on oral administration, and Compounds III, IV and V are further there disclosed to be useful as urinary antiseptic agents on oral administration in mice.
However, there has been no indication or suggestion in the prior art that Compounds I, II, III, IV, and V have immuno stimulating properties.
Natural cellular immunity in the normal host is known to be initiated by contact between an invading foreign antigen (bacteria, virus, protozoa, neoplastic cell, etc.) and thymus-derived lymphocytes (T-cells) which, when stimulated by foreign antigen, release soluble factors (lymphokines) into circulation. These factors or enzymes produced by the T-cells in turn activate the macrophages which destroy the invading organism by a process of phagocytosis followed by a direct attack on the organism by enzymes that dissolve the invading organism (lysosomal enzymes). Organisms such as tubercle bacilli and leprosy bacilli survive phagocytosis and even multiply within nonactivated macrophages. The activated macrophage however destroys these organisms by increased concentrations of lysosomes and lysosomal enzymes [Bennett et al., J. Transplantation, 5, 996-1000].
When the normal host is exposed to overwhelming numbers of invading organisms or its immune response system has been compromised by a deficiency in the immune system, only immune stimulation from sources outside the host can prevent a takeover by the intruder.
In the case of alleviation of allergic or inflammatory diseases, diabetes or essential hypertension, the role of immuno stimulators is less clear. Inflammatory conditions, such as rheumatoid arthritis, are characterized by proliferation in the affected joints of lysozomal enzymes possibly produced in the phagocytic process by the macrophage cells. Alleviation of the inflammatory condition may, in certain conditions, involve suppression, rather than stimulation, of the immune system by the immuno modulator. Thus the same chemical entity may appear to exhibit immuno stimulation as well as immuno depression of the immune response system, depending upon the particular disease condition being alleviated, and it may be more accurate to refer to such entities as immuno modulators rather than immuno stimulants or immuno suppressants, since they are usually capable of behaving in both capacities. (See for example the references given above with respect to use of levamisole as an immuno modulator.)
Chemically induced diabetes in mice or rats has been associated with impairment of cell mediated immunity (Brown et al., T-Cell Function in Diabetic Mice, [Paper No. 5239] Proc. Ann. Meeting Fed. Am. Soc. Exp. Biol. and Med., Chicago, Ill., 1976). This involvement of cellular immunity or the modification of the disease by immuno modulation is not only unexpected but unexplainable with our present knowledge.